tbuckley/cabot-search huggingface dataset:
Immunogenicity and safety of fractional doses of 17D-213 yellow fever vaccine in HIV-infected people in Kenya (YEFE): a randomised, double-blind, non-inferiority substudy of a phase 4 trial
Authors: Derick Kimathi, Aitana Juan-Giner, Benedict Orindi, Kyra H Grantz, Ndeye S Bob, Stanley Cheruiyot, Mainga Hamaluba, Naomi Kamau, Gamou Fall, Moussa Dia, Moses Mosobo, Felix Moki, Kenneth Kiogora, Oscar Chirro, Alexander Thiong'o, Jane Mwendwa, Andrew Guantai, Henry K Karanja, John Gitonga, Daisy Mugo, Kelly Ramko, Ousmane Faye, Eduard J Sanders, Rebecca F Grais, Philip Bejon, George M Warimwe
Journal: The Lancet Infectious Diseases (2023)

Evidence indicates that fractional doses of yellow fever vaccine are safe and sufficiently immunogenic for use during yellow fever outbreaks. However, there are no data on the generalisability of this observation to populations living with HIV. Therefore, we aimed to evaluate the immunogenicity of fractional and standard doses of yellow fever vaccine in HIV-positive adults.
Sex-Biased Expression Is Associated With Chromatin State in Drosophila<i>melanogaster</i>and<i>Drosophila simulans</i>
Authors: Adalena V Nanni, Natalie Martinez, Rita Graze, Alison Morse, Jeremy R B Newman, Vaibhav Jain, Srna Vlaho, Sarah Signor, Sergey V Nuzhdin, Rolf Renne, Lauren M McIntyre
Journal: Molecular Biology and Evolution (2023)

In Drosophila melanogaster and D. simulans head tissue, 60% of orthologous genes show evidence of sex-biased expression in at least one species. Of these, ∼39% (2,192) are conserved in direction. We hypothesize enrichment of open chromatin in the sex where we see expression bias and closed chromatin in the opposite sex. Male-biased orthologs are significantly enriched for H3K4me3 marks in males of both species (∼89% of male-biased orthologs vs. ∼76% of unbiased orthologs). Similarly, female-biased orthologs are significantly enriched for H3K4me3 marks in females of both species (∼90% of female-biased orthologs vs. ∼73% of unbiased orthologs). The sex-bias ratio in female-biased orthologs was similar in magnitude between the two species, regardless of the closed chromatin (H3K27me2me3) marks in males. However, in male-biased orthologs, the presence of H3K27me2me3 in both species significantly reduced the correlation between D. melanogaster sex-bias ratio and the D. simulans sex-bias ratio. Male-biased orthologs are enriched for evidence of positive selection in the D. melanogaster group. There are more male-biased genes than female-biased genes in both species. For orthologs with gains/losses of sex-bias between the two species, there is an excess of male-bias compared to female-bias, but there is no consistent pattern in the relationship between H3K4me3 or H3K27me2me3 chromatin marks and expression. These data suggest chromatin state is a component of the maintenance of sex-biased expression and divergence of sex-bias between species is reflected in the complexity of the chromatin status.
Two Forms of Sexual Dimorphism in Gene Expression in<i>Drosophila melanogaster</i>: Their Coincidence and Evolutionary Genetics
Authors: Amardeep Singh, Aneil F Agrawal
Journal: Molecular Biology and Evolution (2023)

Abstract Phenotypic sexual dimorphism can be mediated by sex differences in gene expression. We examine two forms of sexual dimorphism in gene expression in Drosophila melanogaster: 1) sex-biased gene expression (SBGE) in which the sexes differ in the amount a gene is expressed and 2) sexual dimorphism in isoform usage, that is, sex-specific splicing (SSS). In whole body (but not the head) expression, we find a negative association between SBGE and SSS, possibly suggesting that these are alternate routes to resolving sexual antagonistic selection. Next, we evaluate whether expression dimorphism contributes to the heterogeneity among genes in rmf, the intersexual genetic correlation in body expression that constrains the extent to which a gene's expression can evolve independently between the sexes. We find lower rmf values for genes with than without SSS. We find higher rmf values for male- than female-biased genes (except genes with extreme male bias), even though male-biased genes are known to have greater evolutionary divergence in expression. Finally, we examine population genetic patterns in relation to SBGE and SSS because genes with expression dimorphism have likely experienced a history of sex differences in selection. SSS is associated with reduced values of Tajima's D and elevated direction of selection (DoS) values, suggestive of higher rates of adaptive evolution. Though DoS is highly elevated for genes with extreme male bias, DoS otherwise tends to decline from female-biased to unbiased to male-biased genes. Collectively, the results indicate that SBGE and SSS are differentially distributed across the genome and are associated with different forms of selection.
Micro Germline-Restricted Chromosome in Blue Tits: Evidence for Meiotic Functions
Authors: Jakob C Mueller, Stephen A Schlebusch, Yifan Pei, Manon Poignet, Niki Vontzou, Francisco J Ruiz-Ruano, Tomáš Albrecht, Radka Reifová, Wolfgang Forstmeier, Alexander Suh, Bart Kempenaers
Journal: Molecular Biology and Evolution (2023)

Abstract The germline-restricted chromosome (GRC) is likely present in all songbird species but differs widely in size and gene content. This extra chromosome has been described as either a microchromosome with only limited basic gene content or a macrochromosome with enriched gene functions related to female gonad and embryo development. Here, we assembled, annotated, and characterized the first micro-GRC in the blue tit (Cyanistes caeruleus) using high-fidelity long-read sequencing data. Although some genes on the blue tit GRC show signals of pseudogenization, others potentially have important functions, either currently or in the past. We highlight the GRC gene paralog BMP15, which is among the highest expressed GRC genes both in blue tits and in zebra finches (Taeniopygia guttata) and is known to play a role in oocyte and follicular maturation in other vertebrates. The GRC genes of the blue tit are further enriched for functions related to the synaptonemal complex. We found a similar functional enrichment when analyzing published data on GRC genes from two nightingale species (Luscinia spp.). We hypothesize that these genes play a role in maintaining standard maternal inheritance or in recombining maternal and paternal GRCs during potential episodes of biparental inheritance.
Evaluation of 11C-Choline PET/CT for T Staging and Tumor Volume Delineation in Nasopharyngeal Cancer Patients in Comparison to 18F-FDG PET/CT
Authors: Chunyan Li, Yuhui Yang, Fan Hu, Yuanyuan Xu, Bian Wu, Jing Huang, Kunyu Yang, Xiaoli Lan
Journal: Clinical Nuclear Medicine (2023)

Purpose Accurate determination of the primary tumor extension of nasopharyngeal carcinoma (NPC) by 18 F-FDG PET/CT is limited by the high physiological 18 F-FDG uptake in the surrounding area, especially in the brain tissue. We aimed to assess whether 11 C-choline PET/CT could improve the accuracy of T staging and tumor volume delineation for NPC patients. Methods Patients with pathologically confirmed diagnosis of NPC were enrolled. The primary tumor extension of each patient was evaluated by 11 C-choline PET/CT, 18 F-FDG PET/CT, and contrast-enhanced MRI. The PET/CT-based tumor volume ( V PET ) was measured by 3 threshold methods, including the threshold of SUV 2.5 (Th 2.5 ), 40% of maximal SUV (Th 40% ), and the relative background-dependent threshold (Th bgd ). Tumor volume and Dice similarity coefficient were compared among V PET with different segmentation methods and V MR . Results Thirty-three patients with treatment-naive NPC and 6 patients with suspicious recurrent disease were enrolled. The NPC lesions were avid for both 11 C-choline and 18 F-FDG. Visual analysis showed that 11 C-choline PET/CT had better contrast and higher discernability than 18 F-FDG PET/CT for intracranial, skull base, and orbital involvement. 11 C-choline PET/CT also exhibited advantage over MRI for differentiation between local recurrence and radiation-induced alterations. For the tumor delineated, the V MR was larger than V PET in general, except for 18 F-FDG PET/CT with Th 2.5 threshold. For all 3 threshold methods applied, 11 C-choline PET/CT produced more consistent and comparable tumor volume to MRI than 18 F-FDG PET/CT. 11 C-choline PET/CT with Th bgd threshold showed the closest tumor volume and highest similarity to MRI. Conclusions 11 C-choline PET/CT provides a higher accuracy than 18 F-FDG PET/CT in mapping tumor extension in locally advanced NPC and may be a promising complement to MRI in delineating the primary tumor.
Tumor-Derived Small Extracellular Vesicles Inhibit the Efficacy of CAR T Cells against Solid Tumors
Authors: Wenqun Zhong, Zebin Xiao, Zhiyuan Qin, Jingbo Yang, Yi Wen, Ziyan Yu, Yumei Li, Neil C. Sheppard, Serge Y. Fuchs, Xiaowei Xu, Meenhard Herlyn, Carl H. June, Ellen Puré, Wei Guo
Journal: Cancer Research (2023)

Abstract Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable success in the treatment of hematologic malignancies. Unfortunately, it has limited efficacy against solid tumors, even when the targeted antigens are well expressed. A better understanding of the underlying mechanisms of CAR T-cell therapy resistance in solid tumors is necessary to develop strategies to improve efficacy. Here we report that solid tumors release small extracellular vesicles (sEV) that carry both targeted tumor antigens and the immune checkpoint protein PD-L1. These sEVs acted as cell-free functional units to preferentially interact with cognate CAR T cells and efficiently inhibited their proliferation, migration, and function. In syngeneic mouse tumor models, blocking tumor sEV secretion not only boosted the infiltration and antitumor activity of CAR T cells but also improved endogenous antitumor immunity. These results suggest that solid tumors use sEVs as an active defense mechanism to resist CAR T cells and implicate tumor sEVs as a potential therapeutic target to optimize CAR T-cell therapy against solid tumors. Significance: Small extracellular vesicles secreted by solid tumors inhibit CAR T cells, which provide a molecular explanation for CAR T-cell resistance and suggests that strategies targeting exosome secretion may enhance CAR T-cell efficacy. See related commentary by Ortiz-Espinosa and Srivastava, p. 2637
Alternative splicing of <i>GSDMB</i> modulates killer lymphocyte–triggered pyroptosis
Authors: Qing Kong, Shiyu Xia, Xingxin Pan, Kaixiong Ye, Zhouyihan Li, Haoyan Li, Xiaoqiang Tang, Nidhi Sahni, S. Stephen Yi, Xing Liu, Hao Wu, Michael B. Elowitz, Judy Lieberman, Zhibin Zhang
Journal: Science Immunology (2023)

Granzyme A from killer lymphocytes cleaves gasdermin B (GSDMB) and triggers pyroptosis in targeted human tumor cells, eliciting antitumor immunity. However, GSDMB has a controversial role in pyroptosis and has been linked to both anti- and protumor functions. Here, we found that GSDMB splicing variants are functionally distinct. Cleaved N-terminal (NT) fragments of GSDMB isoforms 3 and 4 caused pyroptosis, but isoforms 1, 2, and 5 did not. The nonfunctional isoforms have a deleted or modified exon 6 and therefore lack a stable belt motif. The belt likely contributes to the insertion of oligomeric GSDMB-NTs into the membrane. Consistently, noncytotoxic GSDMB-NTs blocked pyroptosis caused by cytotoxic GSDMB-NTs in a dominant-negative manner. Upon natural killer (NK) cell attack, GSDMB3-expressing cells died by pyroptosis, whereas GSDMB4-expressing cells died by mixed pyroptosis and apoptosis, and GSDMB1/2-expressing cells died only by apoptosis. GSDMB4 partially resisted NK cell-triggered cleavage, suggesting that only GSDMB3 is fully functional. GSDMB1-3 were the most abundant isoforms in the tested tumor cell lines and were similarly induced by interferon-γ and the chemotherapy drug methotrexate. Expression of cytotoxic GSDMB3/4 isoforms, but not GSDMB1/2 isoforms that are frequently up-regulated in tumors, was associated with better outcomes in bladder and cervical cancers, suggesting that GSDMB3/4-mediated pyroptosis was protective in those tumors. Our study indicates that tumors may block and evade killer cell-triggered pyroptosis by generating noncytotoxic GSDMB isoforms. Therefore, therapeutics that favor the production of cytotoxic GSDMB isoforms by alternative splicing may improve antitumor immunity.
Microneedle‐Mediated Transcutaneous Immunization: Potential in Nucleic Acid Vaccination
Authors: Haochen Wang, Junhua Xu, Lin Xiang
Journal: Advanced Healthcare Materials (2023)

Abstract Efforts aimed at exploring economical and efficient vaccination have taken center stage to combat frequent epidemics worldwide. Various vaccines have been developed for infectious diseases, among which nucleic acid vaccines have attracted much attention from researchers due to their design flexibility and wide application. However, the lack of an efficient delivery system considerably limits the clinical translation of nucleic acid vaccines. As mass vaccinations via syringes are limited by low patient compliance and high costs, microneedles (MNs), which can achieve painless, cost‐effective, and efficient drug delivery, can provide an ideal vaccination strategy. The MNs can break through the stratum corneum barrier in the skin and deliver vaccines to the immune cell‐rich epidermis and dermis. In addition, the feasibility of MN‐mediated vaccination is demonstrated in both preclinical and clinical studies and has tremendous potential for the delivery of nucleic acid vaccines. In this work, the current status of research on MN vaccines is reviewed. Moreover, the improvements of MN‐mediated nucleic acid vaccination are summarized and the challenges of its clinical translation in the future are discussed.
Genetic Modulation of <i>BET1L</i> Confers Colorectal Cancer Susceptibility by Reducing miRNA Binding and m6A Modification
Authors: Shuwei Li, Mulong Du, Kaili Xu, Shuai Ben, Tianru Zhu, Mengfan Guo, Junyi Xin, Lingjun Zhu, Dongying Gu, Zhengdong Zhang, Meilin Wang
Journal: Cancer Research (2023)

Abstract Genetic variants in regions encoding 3′ untranslated regions (UTR) of mRNA potentially alter miRNA binding affinity and N6-methyladenosine (m6A) levels to affect gene expression. A better understanding of the association of these variants with colorectal cancer susceptibility could facilitate development of cancer prevention and treatment approaches. Here, we analyzed miRNA expression profiles and integrated genetic analyses from 8,533 individuals to evaluate the effects of altered miRNA-binding sites on colorectal cancer risk. The single-nucleotide polymorphism rs11245997 in the BET1L 3′UTR was significantly associated with colorectal cancer risk. The rs11245997 A allele facilitated BET1L expression by disrupting miR-140–3p binding. It also reduced BET1L m6A modification, which upregulated BET1L expression levels through a mechanism mediated by the m6A methyltransferases (METTL14 and WTAP) and the m6A demethylase ALKBH5. Moreover, higher expression of BET1L was associated with advanced tumor stages and poor patient prognosis. Increased BET1L expression promoted growth of colorectal cancer cells in vitro and in vivo, which could be partially rescued with miR-140–3p overexpression. RNA sequencing and pathway analyses indicated that BET1L is associated with the steroid biosynthesis pathway through regulation of HSD17B7, CYP27B1, and COMT. These findings provide insights into the involvement of genetic variants of BET1L in the development and progression of colorectal cancer. Significance: The integration of miRNA expression profiles and genetic variants identified rs11245997 as a colorectal cancer risk-related variant that reduces miR-140–3p binding and m6A modification, leading to BET1L upregulation to promote colorectal tumorigenesis.
Bcl11b sustains multipotency and restricts effector programs of intestinal-resident memory CD8 <sup>+</sup> T cells
Authors: Eric Y. Helm, Tomas Zelenka, Valeriu B. Cismasiu, Shamima Islam, Leonardo Silvane, Beatrice Zitti, Tim D. Holmes, Theodore T. Drashansky, Alexander J. Kwiatkowski, Christine Tao, Joseph Dean, Alyssa N. Obermayer, Xianghong Chen, Benjamin G. Keselowsky, Weizhou Zhang, Zhiguang Huo, Liang Zhou, Brian S. Sheridan, Jose R. Conejo-Garcia, Timothy I. Shaw, Yenan T. Bryceson, Dorina Avram
Journal: Science Immunology (2023)

The networks of transcription factors (TFs) that control intestinal-resident memory CD8 + T (T RM ) cells, including multipotency and effector programs, are poorly understood. In this work, we investigated the role of the TF Bcl11b in T RM cells during infection with Listeria monocytogenes using mice with post-activation, conditional deletion of Bcl11b in CD8 + T cells. Conditional deletion of Bcl11b resulted in increased numbers of intestinal T RM cells and their precursors as well as decreased splenic effector and circulating memory cells and precursors. Loss of circulating memory cells was in part due to increased intestinal homing of Bcl11b −/− circulating precursors, with no major alterations in their programs. Bcl11b −/− T RM cells had altered transcriptional programs, with diminished expression of multipotent/multifunctional (MP/MF) program genes, including Tcf7 , and up-regulation of the effector program genes, including Prdm1. Bcl11b also limits the expression of Ahr, another TF with a role in intestinal CD8 + T RM cell differentiation. Deregulation of T RM programs translated into a poor recall response despite T RM cell accumulation in the intestine. Reduced expression of MP/MF program genes in Bcl11b −/− T RM cells was linked to decreased chromatin accessibility and a reduction in activating histone marks at these loci. In contrast, the effector program genes displayed increased activating epigenetic status. These findings demonstrate that Bcl11b is a frontrunner in the tissue residency program of intestinal memory cells upstream of Tcf1 and Blimp1, promoting multipotency and restricting the effector program.
Association Between Bruton's Tyrosine Kinase Gene Overexpression and Risk of Lymphoma in Primary Sjögren's Syndrome
Authors: Pierre‐Marie Duret, Cedric Schleiss, Lou Kawka, Nicolas Meyer, Tao Ye, Alain Saraux, Valérie Devauchelle‐Pensec, Raphaele Seror, Claire Larroche, Aleth Perdriger, Jean Sibilia, Laurent Vallat, Luc‐Matthieu Fornecker, Gaetane Nocturne, Xavier Mariette, Jacques‐Eric Gottenberg
Journal: Arthritis & Rheumatology (2023)

Objective We undertook this study to analyze whole blood gene expression and to investigate the role of B cell genes in primary Sjögren's syndrome–related non‐Hodgkin lymphoma (primary SS‐NHL). Methods Peripheral whole blood samples were collected from 345 well‐phenotyped patients with primary SS enrolled in the prospective Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort. Transcriptomic analysis was performed using human Clariom S Arrays (Affymetrix). In our primary analysis, we considered patients with incident lymphoma (i‐primary SS‐NHL) as the case group and all patients without lymphoma as the comparison group. In our sensitivity analyses, we considered all patients with primary SS‐NHL, including those with a history of lymphoma (h‐primary SS‐NHL), as the case group and primary SS patients without lymphoma, stratified on their risk factors of lymphoma, as the comparison group. Results Twenty‐one patients with primary SS‐NHL (including 8 with i‐primary SS‐NHL and 13 h‐primary SS‐NHL) were eligible for transcriptomic analysis; we compared these patients to 324 primary SS controls without lymphoma, including 110 with moderate to severe disease activity and 61 with no risk factor of lymphoma. Functional clustering analyses revealed an enrichment of genes related to innate and adaptive immunity, including B cell–related genes. Bruton's tyrosine kinase (BTK) and a proliferation‐inducing ligand (APRIL) genes were overexpressed before the occurrence of lymphoma in patients with incident lymphoma compared with patients without lymphoma. In sensitivity analyses, BTK was consistently up‐regulated across all comparisons performed. BTK expression was associated with risk of lymphoma on multivariate analyses, which considered 9 validated predictors of lymphoma in primary SS. Conclusion BTK and APRIL were overexpressed in the peripheral blood of primary SS patients prior to lymphoma. The association between BTK, APRIL, and primary SS‐NHL requires confirmation in other prospective cohorts. image
Use of cytokine-induced killer cell therapy in patients with colorectal cancer: a systematic review and meta-analysis
Authors: Celine Man Ying Li, Yoko Tomita, Bimala Dhakal, Runhao Li, Jun Li, Paul Drew, Timothy Price, Eric Smith, Guy J Maddern, Kevin Aaron Fenix
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The number of clinical studies evaluating the benefit of cytokine-induced killer cell (CIK) therapy, an adoptive immunotherapy, for colorectal cancer (CRC) is increasing. In many of these trials, CIK therapy was coadministered with conventional cancer therapy. The aim of this review is to systematically assess the available literature, in which the majority were only in Chinese, on CIK therapy for the management of CRC using meta-analysis and to identify parameters associated with successful CIK therapy implementation. Methods Prospective and retrospective clinical studies which compared CIK therapy to non-CIK therapy in patients with CRC were searched for electronically on MEDLINE, Embase, China National Knowledge Infrastructure, and Wanfang Data databases. The clinical endpoints of overall survival (OS), progression-free survival (PFS), OS and PFS rates, overall response rate (ORR), and toxicity were meta-analyzed using HR and relative ratio (RR), and subgroup analyses were performed using chi-square (χ 2 ) test and I-squared (I 2 ) statistics for study design, disease stage, cotherapy type, and timing of administration. Results In total, 70 studies involving 6743 patients were analyzed. CIK therapy was favored over non-CIK therapy for OS (HR=0.59, 95% CI: 0.53 to 0.65), PFS (HR=0.55, 95% CI: 0.47 to 0.63), and ORR (RR=0.65, 95% CI: 0.57 to 0.74) without increasing toxicity (HR=0.59, 95% CI: 0.16 to 2.25). Subgroup analyses on OS and PFS by study design (randomized vs non-randomized study design), disease stage (Stage I–III vs Stage IV), cotreatment with dendritic cells (DCs) (CIK vs DC-CIK therapy), or timing of therapy administration (concurrent vs sequential with coadministered anticancer therapy) also showed that the clinical benefit of CIK therapy was robust in any subgroup analysis. Furthermore, cotreatment with DCs did not improve clinical outcomes over CIK therapy alone. Conclusion Compared with standard therapy, patients who received additional CIK cell therapy had favorable outcomes without increased toxicity, warranting further investigation into CIK therapy for the treatment of CRC.